The overall aim of this proposal is to identify and evaluate novel candidate antigens for a vaccine against pediatric falciparum malaria. Children suffer the greatest morbidity and mortality from malaria- yet this age group has not been targeted at the identification stage of vaccine development. Human residents of endemic areas develop protective immunity that limits parasitemia and disease during their first 1-3 years of life, and this naturally acquired human immunity provides an attractive model for vaccine development. In this application, we propose to capitalize on the plasma, and parasitologic, and epidemiologic data which we collected on a previously studied cohort of children and use these materials to identify new vaccine candidates for pediatric P. falciparum. In previous studies, we have developed a differential screening method to identify parasite proteins recognized by antibodies that are uniquely expressed by resistant but not susceptible adults. We now propose to utilize this method to identify parasite proteins that are recognized by resistant, but not susceptible, 2 yr old children. These screening experiments will also be performed in resistant and susceptible 3 yr old children. We have previously performed a longitudinal study of malaria infection during early childhood in Muheza, Tanzania. We will capitalize on plasma and parasitology data already available from this cohort to identify new vaccine candidates for pediatric malaria. Using these materials, we propose to perform differential screening of P. falciparum cDNA expression libraries with plasma pooled from the most resistant individuals and contrasting these results using plasma pooled from the most susceptible children. These initial experiments will identify genes whose protein products are preferentially recognized by antibodies in the sera of children with a high level of naturally acquired resistance to P. falciparum infection. These gene products represent rationally identified vaccine candidates. Subsequent experiments will confirm the relationship between humoral immune recognition of these candidates and resistance to reinfection in a cohort of 1000 children currently being enrolled in a Gates Foundation funded project based in Morogoro, TZN. PUBLIC HEALTH RELEVANCE: P. falciparum malaria is a leading cause of morbidity and mortality in developing countries, infecting hundreds of millions of individuals and killing over one million children in sub-Saharan Africa each year. The overall objective of this proposal is to identify novel vaccine candidates for pediatric falciparum malaria. In this application, we will use sera, parasitologic, and epidemiologic data which we collected on a previously studied cohort of children and use these materials to identify new vaccine candidates for pediatric P. falciparum.